We will study molecular and histologic markers of breast cancer risk in women with benign proliferative breast disease. Specific markers to be evaluated include the T29 to C polymorphism of the TGF-beta1 gene, the type I and II receptors for the TGF-beta cytokines, the phosphorylated Smad2 intracellular signaling molecule, and the ErbB-1 and ErbB-3 receptors of the epidermal growth factor receptor family. We will also study the effect of epithelial hyperplasia lacking atypia on breast cancer risk among African-Americans. We are currently conducting a large retrospective cohort study of women who underwent benign breast biopsy. Paraffin embedded tissue from the entry biopsy of these patients is available. By the end of this project we project that we will have observed 781 breast cancer cases during follow-up among 16,846 study subjects in this cohort. We will expand this cohort to include women from Metro General/Hubbard Hospital in order to increase the number of African-American women available for study. We will conduct a series of nested case-control studies on these women. Women who develop breast cancer on follow-up will be the case patients in these studies. Two controls will be selected for each case matched on age and year of biopsy. PCR and immunohistochemical methods will be used to study gene polymorphisms and abnormal protein expression, respectively. Conditional logistic regression analysis will be used to assess the individual and combined effects of molecular, histologic and epidemiologic variables on breast cancer risk. This project will permit the combination of modern methods in molecular biology, pathology and epidemiology to assess potentially powerful new markers of breast cancer prognosis, and may lead to important advances in the prevention and treatment of this disease.